Association of 24-h urinary sodium excretion with microalbuminuria in a Chinese population

To assess the relationship of sodium, potassium and the ratio of sodium to potassium (Na/K) with albuminuria, a cross-sectional study was carried out in China in 2017. Sodium, potassium and albumin excretions were examined in a 24-h (h) urine sample collected from 1486 participants. Microalbuminuria was defined as 24-h urinary albumin excretion between 30 and 300 mg/24 h. The participants had an average age of 46.2 ± 14.1 years old, and 48.9% were men. The proportion of patients with microalbuminuria was 9.0%. As illustrated by the adjusted generalized linear mixed model, sodium concentration increased significantly with the increase in 24-h urinary albumin (β = 1.16, 95% confidence interval (CI) 0.38–1.93; P = 0.003). Multivariable-adjusted logistic regression analyses demonstrated that the odds ratio (OR) of microalbuminuria increased with the quartiles of sodium [OR = 2.20, 95% CI 1.26–3.84 (the maximum quartile vs. the minimum quartile), Pfor trend = 0.006]. Potassium and the Na/K ratio did not have any association with outcome indicators. A high amount of sodium intake was potentially correlated with early renal function impairment.

Statistical analysis. Continuous data were expressed as the mean (M) ± standard deviation (SD), while categorical data were presented as frequency (n) and percentage (%). A t test or chi-squared test was adopted to compare demographic, socioeconomic and clinical variables across subjects with and without microalbuminuria.
Linear mixed models were employed for the associations of urinary albumin level with the sodium, potassium (each 1000 mg), and Na/K ratio (each 1-unit molar ratio). A multivariable logistic regression model was employed to estimate the odds ratio (OR) and 95% confidence interval (CI) for the associations of microalbuminuria with the quartiles of sodium, potassium or Na/K ratio under the circumstance of the lowest quartile as a reference group, and linear trends were tested by calculating the index of sodium, potassium and Na/K ratio as a continuous variable. Two covariate-adjusted models were used in both linear and logistic regression analyses.
Model 1 was adjusted for sex and age, and model 2 was further adjusted for BMI, SBP, alcohol consumption, smoking, physical activities, diabetes, and antihypertensive medication use.
Sensitivity analyses were performed to exclude subjects diagnosed with CVD or taking any drugs, including anti-hypertension, diuretics, vasodilators and sedative drugs, on the interview day, as well as those who met both of the above conditions. Two-side P values < 0.05 were considered significant. Analyses were performed using the SAS statistical package (version 9.2; SAS Institute, Inc., Cary, North Carolina, USA).

Results
The baseline characteristics of 1486 participants with or without microalbuminuria are given in Table 1. The age of the participants was 46.2 ± 14.1 years old, and 48.9% were men. The proportion of microalbuminuria was 9.0%. Different from the participants without microalbuminuria, those with microalbuminuria had a higher possibility of being drinkers, had a higher waist circumference and higher serum triglyceride (TG) level, had higher sodium intake and were more likely to develop hypertension, diabetes, obesity and dyslipidemia.
In the adjusted linear regression models, 24-h sodium excretion was significantly related to 24-h urinary albumin excretion (1.16 mg/24 h; 95% CI 0.38-1.93) for each 1-g increase in sodium excretion (Table 2). There was no significant association of potassium or the Na/K ratio with 24-h urinary albumin excretion in any model. Table 3 presents the adjusted OR and 95% CI of microalbuminuria in the multivariable adjusted logistic model with the lowest quartile as a reference for sodium, potassium and the Na/K ratio. After completely adjusting for the confounding factors in model 2, the ORs of the fourth quartile of sodium were still significantly associated with microalbuminuria (OR = 2.20, 95% CI: 1.26-3.84). The ORs of potassium and the Na/K ratio quartiles remained insignificant in all models. Table 4 and Fig. 1 show that the results of sodium and microalbuminuria are consistent and significant in subgroup analyses for subjects who are male, age ≥ 60 years and < 60 years, nondrinkers, nonsmokers, normal weight, hypertensive, diabetic, dyslipidemia, and use of antihypertensive drugs. No interaction between variables was observed.
The sensitivity analyses showed no change in ORs between sodium and microalbuminuria after exclusion of patients with CVD or using any drugs, including anti-hypertensive drugs, diuretics, vasodilators and sedative drugs, on the interview day, as well as those who met the above conditions (Table 5).

Discussion
This study reports the cross-sectional relationship between 24-h urinary sodium and microalbuminuria in a population-based study in China, which is independent of many other variables, especially blood pressure and antihypertensive drugs.
In the Prevention of Renal and Vascular End Stage Disease (PREVEND) study 7 , the researchers found that after adjusting for confounders, when the sodium intake increased by 1 g, the urinary albumin excretion increased by 4.6 mg/d; In the current study, every 1-g increase in sodium led to an increase in urinary albumin excretion by 1.16 mg/d. This difference may depend on the characteristics of the study participants. Studies by du Cailar et al. 15 , Sun et al. 3 and Xu et al. 16 revealed that 24-h urinary sodium is a strong and independent determinant of urinary albumin excretion. In several studies, a significant correlation between sodium intake www.nature.com/scientificreports/ and proteinuria was found regardless of blood pressure, which demonstrated that blood pressure was not the only reason for the harmful sodium effect. On the other hand, our study showed that potassium intake and the Na/K ratio had no relationship with microalbuminuria. Previous studies have drawn controversial conclusions on the associations between potassium intake, the Na/K ratio and albuminuria. In the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study based on food frequency questionnaires, no association of albuminuria with potassium intake was found 8 . A recent study found that higher 24-h urinary potassium excretion was associated with a lower risk   17 , and another study showed that higher dietary potassium intake was associated with kidney disease progression in CKD patients 18 . The Na/K ratio may be an important indicator of CKD and estimated glomerular filtration rate (eGFR) decline in addition to sodium or potassium alone 19 . However, relevant findings on the impact of the Na/K ratio on kidney function are limited. A cohort study showed that estimated 24-h urinary sodium excretion and the Na/K ratio from spot urine were predictors of kidney function decline measured by eGFR 20 . Another cohort study found that a high self-reported dietary Na/K ratio was associated with an increased risk of incident CKD 19 . A cross-sectional study in China concluded that a high urinary Na/K ratio was associated with albuminuria, a sign of early renal impairment 3 . In contrast, the Shangdong-Ministry of Health Action on Salt and Hypertension (SMASH) study conducted in Chinese individuals found no association between urinary potassium or the Na/K ratio and albuminuria in a general population 21 . Furthermore, a longitudinal Japanese study did not recommend the Na/K ratio from spot urine as a good marker in assessing renal function decline 22 . These inconsistent conclusions may be due to different characteristics of the study population, different measures of sodium and potassium (i.e., spot urine collections, single 24-h urine collections, and food frequency questionnaires) and different indicators of kidney function assessed. Furthermore, low potassium intake in China might be part of the reason for this phenomenon 23 . Nearly all of the participants in the study had potassium intake below the World Health Organization (WHO)'s recommended Figure 1. The relationship between the maximum quartile of urinary sodium excretion and microalbuminuria: odds ratio (OR) with 95% confidence interval (CI) in the whole study and in selected subgroups. Analyses were controlled for age, sex, smoking, drinking, physical activity, BMI, hypertension, diabetes, dyslipidemia, and use of antihypertensive drugs. Table 5. Sensitivity analyses: Adjusted odds ratios (OR) and 95% confidence intervals (CI) for microalbuminuria according to the quartiles of the 24-h urinary sodium excretion. Group A with cardiovascular disease (stroke, coronary heart disease); Group B using anti-hypertensive drugs, diuretics, vasodilators and sedative drugs on the interview day. www.nature.com/scientificreports/ minimum of 3.5 g/d 24 . Individuals who had a higher mean urinary sodium excretion may not have lower mean urinary potassium excretion. Therefore, it was unexpected that no significant association was observed between urinary potassium, the Na/K ratio and albuminuria in this Chinese population-based study. Further exploration of this issue in our future cohort studies with more repeated measurements should be conducted. The biological mechanism of the effect of sodium and potassium on kidney function remains unclear. The positive correlation between urinary sodium excretion and urinary albumin excretion may be due to the adverse effect of sodium on the arterial vessel wall 25 . Increased urinary albumin loss is considered to be a result of endothelial injury. Endothelial injury may lead to increased susceptibility to cardiovascular and renal diseases in subjects with microalbuminuria. High potassium intake was shown to reduce vascular resistance, decrease blood pressure and increase eGFR by directly improving kidney function and therefore may play a protective role in the incidence of albuminuria 19 .
Drugs such as angiotensin receptor blockers, diuretics, and angiotensin-converting enzyme inhibitors can have a great influence on 24-h urinary sodium levels. The use of these drugs has a greater possibility of occurring in people with the highest risk of CVD, so the potential for measurement error is greater 26 . Therefore, people with CVD and those who used any antihypertensive drugs, diuretics, vasodilators or sedative drugs were excluded from the sensitivity analyses to assess study robustness.
The strengths of the study include a large randomized sample of the Chinese population, completion of follow-up, a relatively robust method to evaluate population sodium intake and 24-h urinary albumin excretion through 24-h urine collection, an adequate sample size, and a rigorous approach to control measurement errors.
Our study has some limitations. The results were based on only one-time 24-h urine collection to minimize the burden for participants and the cost for our study. The potential individual differences in sodium intake may be overestimated, and therefore, the advantage of sodium and potassium intake related to albuminuria might be underestimated. Finally, this is a cross-sectional study, although the results were adjusted for major confounders.
In summary, our study showed independent and positive associations of high sodium excretion with microalbuminuria in the general population. With several preventive measures adopted, health-oriented policies for the purpose of reducing sodium intake in the population can relieve not only the burden of albuminuria but also other related disorders.

Data availability
The data that support the findings of our study are not publicly available due to the issue of copyright but are available from the corresponding author upon reasonable request.